THIS issue of the Journal contains a very exciting clinical report that describes the clinical efficacy of epidural sufentanil and neostigmine in laboring women.1
The authors examined the analgesic effects of different combinations of the two drugs without local anesthetic during the first stage of oxytocin-augmented labor. They found that a mixture of 10 μg of sufentanil with 500 μg of neostigmine seemed to be optimal based on onset, duration of action, and minimal motor block.
Efficient labor analgesia without local anesthetics may have important consequences. Research conducted over the last 20 years has resulted in excellent analgesic recipes, typically combining a very low concentration of a long acting local anesthetic with a lipid-soluble opioid. Such combinations provide near-ideal clinical conditions: low pain scores, minimal motor block (allowing ambulation), stable hemodynamics (as a result of minimal sympathetic block),2
and essentially no measurable effects on obstetric outcome.3
Some might actually consider the search for better analgesic techniques to be pointless, given the efficacy of the current approaches.
However, local anesthetics are imperfect drugs. Even at low doses, their use may have catastrophic consequences.4–7
Moreover, although cesarean deliveries resulting from motor block are uncommon, instrumental delivery is required more frequently when regional analgesia is used. In a recent meta-analysis, the rate of instrumental delivery was almost doubled in patients receiving low dose epidural local anesthetic solutions as compared with systemic opioid analgesia.8
There is thus a need for analgesic drugs devoid of motor block effect. That neostigmine (the only cholinesterase inhibitor clinically available for spinal use) is one such candidate may be surprising for most of us who have followed the 15-year history of research with this agent. After experimental studies that found that muscarinic receptors and cholinergic pathways are involved in the spinal control of pain,9
further studies confirmed the analgesic efficacy and the safety (i.e.
, the absence of neurotoxic complications) of intrathecal neostigmine in humans.10–14
However, enthusiasm rapidly declined because of the high incidence and sometimes extreme severity of nausea and vomiting.10,12
Because both spinally and epidurally administered drugs mainly act at the spinal level, it is thus difficult to understand the rationale for testing epidural neostigmine. Fortunately, such skepticism did not dissuade researchers who have now shown that after epidural administration, neostigmine-induced analgesia is not associated with emetic complications, thus rehabilitating our interest in cholinergic analgesic pathways. Several trials from various countries and using different acute/pain chronic settings have confirmed that the risk/benefit ratio is excellent with epidural neostigmine.15–18
Although epidural neostigmine cannot be used as the sole analgesic because its potency is limited, it can provide excellent pain relief when combined with an opioid.19
Because women are believed to experience better neostigmine-induced analgesia than men,20
obstetrics may represent an ideal setting for the drug. In addition, neostigmine is an old and inexpensive drug, thus facilitating its use in the current period of economic constraints.
Should the results of Roelants and Lavand’homme lead us to the routine use of epidural neostigmine in all laboring women? Certainly not. Many questions remain unanswered, and additional studies are clearly needed. One major question lies in the safety of the drug. Although there are two trials (in three animal species) demonstrating the absence of neurotoxicity,13,14
the drug has been used in only a few hundred human subjects and it is likely that regulatory agencies in most countries will require much more data before concluding that epidurally injected neostigmine is truly safe. An additional concern lies in the analgesic potency of the drug. In the study presented in this issue of Anesthesiology, the analgesia produced by the epidural sufentanil-neostigmine combination was similar to that achieved with 20 μg dose of sufentanil alone. Although this is an interesting result, it is of note that the dose of sufentanil used a comparator is the ED50
, the dose which provides adequate analgesia in only 50% of patients. Clearly, before abandoning local anesthetics, one must ensure that neostigmine can reliably provide adequate analgesia in all patients. Moreover, as this was a single-dose study, its efficacy for the whole duration of labor remains uncertain. Will the drug provide adequate analgesia when used as an infusion or will it require top-ups? Will tachyphylaxis occur? Will adverse effects occur (especially fetal effects secondary to placental transfer)21
after repeated administration and larger doses? Will sedation become a concern?22
Will muscle weakness become apparent after prolonged administration?10
These questions, only a few of those remaining, will require a substantial amount of added work to resolve. As with all good studies, questions remaining are more numerous than answers provided. Nevertheless, epidural neostigmine provides an exciting opportunity to increase our knowledge on spinally mediated analgesia and to improve our patients’ comfort.
Dan Benhamou, M.D.
Professor and Chairman, Department of Anesth-esia and Intensive Care, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. email@example.com
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2.Kubli M, Shennan AH, Seed PT, O’Sullivan G: A randomised controlled trial of fluid pre-loading before low dose epidural analgesia for labour. Int J Obstet Anesth 2003; 12:256–60
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8.Sharma SK, McIntire DD, Wiley J, Leveno KJ: Labor analgesia and cesarean delivery: an individual patient meta-analysis of nulliparous women. Anesthesiology 2004; 100:142–8
9.Gordh T Jr, Jansson I, Hartvig P, Gillberg PG, Post C: Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing. Acta Anaesthesiol Scand 1989; 33:39–47
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11.Hood DD, Eisenach JC, Tong C, Tommasi E, Yaksh TL: Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methylsulfate, clonidine and their combination in sheep. Anesthesiology 1995; 82:428–35
12.Shafer SL, Eisenach JC, Hood DD, Tong C: Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1998; 89:1074–88
13.Eisenach JC, Hood DD, Curry R: Phase I human safety assessment of intrathecal neostigmine containing methyl- and propylparabens. Anesth Analg 1997; 85:842–6
14.Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC: Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995; 82:412–27
15.Turan A, Memis D, Basaran U, Karamanlioglu B, Süt N: Caudal ropivacaine and neostigmine in pediatric surgery. Anesthesiology 2003; 98:719–22
16.Lauretti GR, de Oliveira R, Reis MP, Juliao MC, Pereira NL: Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999; 90:1534–8
17.Nakayama M, Ichinose H, Nakabayashi K, Satoh O, Yamamoto S, Namiki A: Analgesic effect of epidural neostigmine after abdominal hysterectomy. J Clin Anesth 2001; 13:86–9
18.Lauretti GR, Gomes JM, Reis MP, Pereira NL: Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999; 11:663–8
19.Naguib M, Yaksh TL: Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with mu and alpha 2 receptor systems. Anesthesiology 1994; 80:1338–48
20.Chiari A, Tobin JR, Pan HL, Hood DD, Eisenach JC: Sex differences in cholinergic analgesia I: A supplemental nicotinic mechanism in normal females. Anesthesiology 1999; 91:1447–54
21.Clark RB, Brown MA, Lattin DL: Neostigmine, atropine and glycopyrrolate: does neostigmine cross the placenta. Anesthesiology 1996; 84:450–2
22.Kaya FN, Sahin S, Owen MD, Eisenach JC: Epidural neostigmine produces analgesia but also sedation in women after cesarean delivery. Anesthesiology 2004; 100:381–5
© 2004 American Society of Anesthesiologists, Inc.